Protein acetylation-dependent fatty acid metabolic dysfunction in HFpEF

HFpEF 中蛋白质乙酰化依赖性脂肪酸代谢功能障碍

• 批准号: 10557911
• 负责人: Dan Tong
• 金额: $ 14.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557911
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Acetyl-CoA C-Acetyltransferase; Acetylation; Acetyltransferase; Agonist; Attenuated; Biological Assay; Cardiac; Cardiovascular Manifestation; Cardiovascular system; Clinical; Coenzyme A; Complement; Coupled; Data; Deacetylase; Defect; Diabetes Mellitus; EFRAC; Enoyl-CoA Hydratase; Enzymes; Equilibrium; Fatty Acids; Foundations; Functional disorder; Health Expenditures; Heart; Heart failure; High Fat Diet; Human; Hypertension; Immunoprecipitation; Impairment; In Vitro; Investigation; Knock-out; Knowledge; Laboratories; Link; Lysine; Mass Spectrum Analysis; Mechanical Stress; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial Proteins; Morbidity - disease rate; Mus; Myocardium; Neurodegenerative Disorders; Nicotinamide adenine dinucleotide; Nitric Oxide Synthase; Obesity; Oral; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Post-Translational Protein Processing; Pre-Clinical Model; Protein Acetylation; Proteins; Proteomics; Research; Research Personnel; Research Project Grants; Rodent; Role; Scheme; Scientist; Secondary to; Sirtuins; Source; Stress; Syndrome; Testing; Therapeutic Effect; Tissues; Training; Work; acyl-CoA dehydrogenase; arginine methyl ester; career; effective therapy; experimental study; fatty acid oxidation; gain of function; hypertensive; insight; loss of function; mitochondrial dysfunction; mortality; mouse model; nicotinamide-beta-riboside; novel; novel therapeutics; preservation; protein function; skills; therapeutic target

Project Summary Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of all patients with heart failure, and is associated with significant morbidity, mortality, and health care expenditures. Yet, no effective treatment for HFpEF has been identified. Commonly coexisting with other metabolic diseases, HFpEF is considered the cardiovascular manifestation of a systemic metabolic disturbance. However, little is known about its underlying mechanisms. Our laboratory recently developed and validated a novel mouse model that faithfully recapitulates most clinical features of human HFpEF. Using this novel mouse model, I discovered significant mitochondrial dysfunction in HFpEF myocardium, which is associated with mitochondrial protein hyperacetylation, a key post- translational modification known to regulate enzymatic activities. This led to our central hypothesis that protein hyperacetylation is a reversible driver of mitochondrial dysfunction and metabolic remodeling in HFpEF and could serve as a meaningful therapeutic target. In this proposal, we aim to (1) Determine the role of Sirtuin 3, the major mitochondrial deacetylase, in regulating mitochondrial function and HFpEF pathogenesis; (2) Identify specific targets through which hyperacetylation impacts mitochondrial function in HFpEF; (3) Determine the therapeutic effect of modulating protein acetylation on HFpEF mitochondrial function and cardiac phenotype. Collectively, these studies will have a meaningful impact on our understanding of HFpEF pathophysiology and potentially unveil novel therapy to effectively treat HFpEF. Furthermore, work proposed here, coupled with a comprehensive training plan, will provide me with the additional knowledge and skills required to launch my career as a successful and fully independent physician-scientist.

项目摘要 射血分数保留的心力衰竭（HFpEF）占所有心力衰竭患者的约50%， 与显著的发病率、死亡率和卫生保健支出相关。然而，没有有效的治疗方法， HFpEF已确定。HFpEF通常与其他代谢性疾病共存，被认为是 全身代谢紊乱的心血管表现。然而，人们对它的基本原理知之甚少。 机制等我们的实验室最近开发并验证了一种新的小鼠模型， 人HFpEF的大多数临床特征。使用这种新的小鼠模型，我发现了显著的线粒体 HFpEF心肌功能障碍，这与线粒体蛋白过度乙酰化有关，这是一个关键的后 翻译修饰已知调节酶活性。这导致了我们的核心假设， 高乙酰化是HFpEF中线粒体功能障碍和代谢重塑的可逆驱动因素， 作为一个有意义的治疗目标。在这项建议中，我们的目标是（1）确定Sirtuin 3的作用，主要是 线粒体去乙酰化酶，在调节线粒体功能和HFpEF发病机制中的作用;（2）鉴定特异性 高乙酰化通过其影响HFpEF中线粒体功能的靶点;（3）确定治疗 调节蛋白乙酰化对HFpEF线粒体功能和心脏表型影响。总的来说， 这些研究将对我们理解HFpEF的病理生理学产生有意义的影响， 揭示了有效治疗HFpEF的新疗法。此外，这里提出的工作，加上全面的 培训计划，将为我提供额外的知识和技能，需要启动我的职业生涯， 成功的、完全独立的医学科学家。